Macrophage Infiltration of Skin Lesions Correlates to Prognosis of Gvhd; A Clue to Refractory Gvhd

The pathophysiology of acute graft-versus-host disease (aGVHD) is a complex process. Although it is considered an alloimmune attack on host tissues mounted mainly by donor CD8-positive T cells, skin infiltration of T cells is not always the case in biopsy specimens of skin aGVHD, suggesting the involvement of other cellular components. In detailed observation, CD163-positive macrophages which have abilities of antigen presentation and releasing cytokines were frequently observed. We retrospectively reviewed 66 biopsy specimens of skin lesions clinically thought to be aGVHD performed within 100 days after allogeneic stem cell transplantation, and analyzed the relationship between types of infiltrating cells and clinical outcomes. Paraffin-section immunohistochemical analysis was performed using a monoclonal antibody against CD8 and CD163. Counting the total number of CD8-positive T cells and CD163-positive macrophages in 4 fields with 200-fold magnification, median number of CD-8 positive T cells was 78.5 (range; 2–305), and that of CD163-positive macrophages was 149 (range; 38–372). Infiltration of over 100 cells of CD8-positive T cells (CD8ov100) correlated with HLA class I mismatch and grade III–IV a GVHD, while infiltration of over 200 cells of CD163-positive macrophages (CD163ov200) correlated with grade III–IV aGVHD and refractory aGVHD. In logistic analyses, CD163ov200 (Odds 6.29 (95%CI 1.57–25.0); p=0.009) was identified as the only negative predictors of aGHVD outcome. Overall survival of patients with CD163ov200 was significantly lower than that of those with infiltration of under 200 cells of CD163-positive macrophages (63.0% vs. 40.6% at 1 year, respectively; p=0.02). In 23 patients treated with steroid for aGVHD, CD163ov200 was the only significant predictor of refractory aGVHD outcome (Odds 10.9 (95%CI 1.37–83.3); p=0.02), and overall survival of patients with CD163ov200 was significantly lower than that of those with infiltration of under 200 cells of CD163-positive macrophages (63.5% vs. 12.5% at 1 year, respectively; p=0.0004). These results indicate that CD163-positive macrophages may provide a clue for the pathophysiology of refractory GVHD and new treatment strategies.